tbuckley/cabot-search huggingface dataset:
The promise of machine learning applications in solid organ transplantation
Authors: Neta Gotlieb, Amirhossein Azhie, Divya Sharma, Ashley Spann, Nan-Ji Suo, Jason Tran, Ani Orchanian-Cheff, Bo Wang, Anna Goldenberg, Michael Chassé, Heloise Cardinal, Joseph Paul Cohen, Andrea Lodi, Melanie Dieude, Mamatha Bhat
Journal: npj Digital Medicine (2022)

Abstract Solid-organ transplantation is a life-saving treatment for end-stage organ disease in highly selected patients. Alongside the tremendous progress in the last several decades, new challenges have emerged. The growing disparity between organ demand and supply requires optimal patient/donor selection and matching. Improvements in long-term graft and patient survival require data-driven diagnosis and management of post-transplant complications. The growing abundance of clinical, genetic, radiologic, and metabolic data in transplantation has led to increasing interest in applying machine-learning (ML) tools that can uncover hidden patterns in large datasets. ML algorithms have been applied in predictive modeling of waitlist mortality, donor–recipient matching, survival prediction, post-transplant complications diagnosis, and prediction, aiming to optimize immunosuppression and management. In this review, we provide insight into the various applications of ML in transplant medicine, why these were used to evaluate a specific clinical question, and the potential of ML to transform the care of transplant recipients. 36 articles were selected after a comprehensive search of the following databases: Ovid MEDLINE; Ovid MEDLINE Epub Ahead of Print and In-Process &amp; Other Non-Indexed Citations; Ovid Embase; Cochrane Database of Systematic Reviews (Ovid); and Cochrane Central Register of Controlled Trials (Ovid). In summary, these studies showed that ML techniques hold great potential to improve the outcome of transplant recipients. Future work is required to improve the interpretability of these algorithms, ensure generalizability through larger-scale external validation, and establishment of infrastructure to permit clinical integration.
Variational Phylodynamic Inference Using Pandemic-scale Data
Authors: Caleb Ki, Jonathan Terhorst
Journal: Molecular Biology and Evolution (2022)

The ongoing global pandemic has sharply increased the amount of data available to researchers in epidemiology and public health. Unfortunately, few existing analysis tools are capable of exploiting all of the information contained in a pandemic-scale data set, resulting in missed opportunities for improved surveillance and contact tracing. In this paper, we develop the variational Bayesian skyline (VBSKY), a method for fitting Bayesian phylodynamic models to very large pathogen genetic data sets. By combining recent advances in phylodynamic modeling, scalable Bayesian inference and differentiable programming, along with a few tailored heuristics, VBSKY is capable of analyzing thousands of genomes in a few minutes, providing accurate estimates of epidemiologically relevant quantities such as the effective reproduction number and overall sampling effort through time. We illustrate the utility of our method by performing a rapid analysis of a large number of SARS-CoV-2 genomes, and demonstrate that the resulting estimates closely track those derived from alternative sources of public health data.
Monkeypox outbreak in Madrid (Spain): Clinical and virological aspects
Authors: Eva Orviz, Anabel Negredo, Oskar Ayerdi, Ana Vázquez, Ana Muñoz-Gomez, Sara Monzón, Petunia Clavo, Angel Zaballos, Mar Vera, Patricia Sánchez, Noemi Cabello, Pilar Jiménez, Jorge A. Pérez-García, Sarai Varona, Jorge del Romero, Isabel Cuesta, Alberto Delgado-Iribarren, Montse Torres, Iñigo Sagastagoitia, Gustavo Palacios, Vicente Estrada, Maria Paz Sánchez-Seco, Juan Ballesteros, Begoña Baza, Juan Carlos Carrió, Cynthia Chocron, Giovanni Fedele, Cristina García-Amil, Laura Herrero, Reynaldo Homen, Alberto Mariano, Teresa Martínez-Burgoa, Francisca Molero, Maria Luisa Navarro, Maria José Núñez, Juncal Perez-Somarriba, Teresa Puerta, Javier Rodríguez-Añover, Esperanza Pérez Pastrana, Mercedes Jiménez, Leticia de la Vega, Jorge Vergas, Isabel Zarza
Journal: Journal of Infection (2022)
A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells
Authors: Mariangela Russo, Simone Pompei, Alberto Sogari, Mattia Corigliano, Giovanni Crisafulli, Alberto Puliafito, Simona Lamba, Jessica Erriquez, Andrea Bertotti, Marco Gherardi, Federica Di Nicolantonio, Alberto Bardelli, Marco Cosentino Lagomarsino
Journal: Nature Genetics (2022)

Compelling evidence shows that cancer persister cells represent a major limit to the long-term efficacy of targeted therapies. However, the phenotype and population dynamics of cancer persister cells remain unclear. We developed a quantitative framework to study persisters by combining experimental characterization and mathematical modeling. We found that, in colorectal cancer, a fraction of persisters slowly replicates. Clinically approved targeted therapies induce a switch to drug-tolerant persisters and a temporary 7- to 50-fold increase of their mutation rate, thus increasing the number of persister-derived resistant cells. These findings reveal that treatment may influence persistence and mutability in cancer cells and pinpoint inhibition of error-prone DNA polymerases as a strategy to restrict tumor recurrence.
In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation
Authors: Chiara Anania, Rafael D. Acemel, Johanna Jedamzick, Adriano Bolondi, Giulia Cova, Norbert Brieske, Ralf Kühn, Lars Wittler, Francisca M. Real, Darío G. Lupiáñez
Journal: Nature Genetics (2022)

Abstract Vertebrate genomes organize into topologically associating domains, delimited by boundaries that insulate regulatory elements from nontarget genes. However, how boundary function is established is not well understood. Here, we combine genome-wide analyses and transgenic mouse assays to dissect the regulatory logic of clustered-CCCTC-binding factor (CTCF) boundaries in vivo, interrogating their function at multiple levels: chromatin interactions, transcription and phenotypes. Individual CTCF binding site (CBS) deletions revealed that the characteristics of specific sites can outweigh other factors such as CBS number and orientation. Combined deletions demonstrated that CBSs cooperate redundantly and provide boundary robustness. We show that divergent CBS signatures are not strictly required for effective insulation and that chromatin loops formed by nonconvergently oriented sites could be mediated by a loop interference mechanism. Further, we observe that insulation strength constitutes a quantitative modulator of gene expression and phenotypes. Our results highlight the modular nature of boundaries and their control over developmental processes.
Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline
Authors: Navneet Singh, Sarah Temin, Sherman Baker, Elizabeth Blanchard, Julie R. Brahmer, Paul Celano, Narjust Duma, Peter M. Ellis, Ivy B. Elkins, Rami Y. Haddad, Paul J. Hesketh, Dharamvir Jain, David H. Johnson, Natasha B. Leighl, Hirva Mamdani, Gregory Masters, Pamela R. Moffitt, Tanyanika Phillips, Gregory J. Riely, Andrew G. Robinson, Rafael Rosell, Joan H. Schiller, Bryan J. Schneider, David R. Spigel, Ishmael A. Jaiyesimi
Journal: Journal of Clinical Oncology (2022)

Living guidelines are routinely updated guidelines that are developed for selected topic areas with rapidly evolving evidence that drives frequent change in clinical practice. These guidelines are updated on a regular schedule, based on the work of a standing panel that reviews the literature on a continuous basis. Updates will be made regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline . PURPOSE To provide evidence-based recommendations updating the 2021 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) with driver alterations. METHODS ASCO updated recommendations on the basis of an ongoing systematic review of randomized control trials from 2020 to 2021. RESULTS This guideline update reflects changes in evidence since the previous update. Two studies provide the evidence base. Outcomes of interest include efficacy and safety. RECOMMENDATIONS For patients with an anaplastic lymphoma kinase rearrangement, a performance status (PS) of 0-2, and previously untreated NSCLC, clinicians should offer alectinib or brigatinib or lorlatinib. For patients with an anaplastic lymphoma kinase rearrangement, a PS of 0-2, and previously untreated NSCLC, if alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib. For patients with a RET rearrangement, a PS of 0-2, and previously untreated NSCLC, clinicians may offer selpercatinib or pralsetinib. In second line, for patients with a RET rearrangement who have not received RET-targeted therapy, clinicians may offer selpercatinib or pralsetinib. Additional information is available at www.asco.org/thoracic-cancer-guidelines .
Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease
Authors: Takafumi Kato, Takanori Asakura, Caitlin E. Edwards, Hong Dang, Yu Mikami, Kenichi Okuda, Gang Chen, Ling Sun, Rodney C. Gilmore, Padraig Hawkins, Gabriela De la Cruz, Michelle R. Cooley, Alexis B. Bailey, Stephen M. Hewitt, Daniel S. Chertow, Alain C. Borczuk, Steven Salvatore, Fernando J. Martinez, Leigh B. Thorne, Frederic B. Askin, Camille Ehre, Scott H. Randell, Wanda K. O’Neal, Ralph S. Baric, Richard C. Boucher
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: The incidence and sites of mucus accumulation and molecular regulation of mucin gene expression in coronavirus (COVID-19) lung disease have not been reported. Objectives: To characterize the incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. Methods: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by Alcian blue and periodic acid-Schiff staining, immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected human bronchial epithelial (HBE) cultures were used to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. Measurements and Main Results: MUC5B and variably MUC5AC RNA concentrations were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the subacute/chronic disease phase after SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of subjects with COVID-19 in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days after inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days after inoculation. SARS-CoV-2 infection of HBE cultures induced expression of epidermal growth factor receptor (EGFR) ligands and inflammatory cytokines (e.g., IL-1α/β) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways or administration of dexamethasone reduced SARS-CoV-2-induced mucin expression. Conclusions: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation after SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease.
Tissue Engineering Cartilage with Deep Zone Cytoarchitecture by High‐Resolution Acoustic Cell Patterning
Authors: James P. K. Armstrong, Ekaterina Pchelintseva, Sirli Treumuth, Cristiana Campanella, Christoph Meinert, Travis J. Klein, Dietmar W. Hutmacher, Bruce W. Drinkwater, Molly M. Stevens
Journal: Advanced Healthcare Materials (2022)

Abstract The ultimate objective of tissue engineering is to fabricate artificial living constructs with a structural organization and function that faithfully resembles their native tissue counterparts. For example, the deep zone of articular cartilage possesses a distinctive anisotropic architecture with chondrocytes organized in aligned arrays ≈1–2 cells wide, features that are oriented parallel to surrounding extracellular matrix fibers and orthogonal to the underlying subchondral bone. Although there are major advances in fabricating custom tissue architectures, it remains a significant technical challenge to precisely recreate such fine cellular features in vitro. Here, it is shown that ultrasound standing waves can be used to remotely organize living chondrocytes into high‐resolution anisotropic arrays, distributed throughout the full volume of agarose hydrogels. It is demonstrated that this cytoarchitecture is maintained throughout a five‐week course of in vitro tissue engineering, producing hyaline cartilage with cellular and extracellular matrix organization analogous to the deep zone of native articular cartilage. It is anticipated that this acoustic cell patterning method will provide unprecedented opportunities to interrogate in vitro the contribution of chondrocyte organization to the development of aligned extracellular matrix fibers, and ultimately, the design of new mechanically anisotropic tissue grafts for articular cartilage regeneration.
Artificial Intelligence Allows Leaving-In-Situ Colorectal Polyps
Authors: Cesare Hassan, Giuseppina Balsamo, Roberto Lorenzetti, Angelo Zullo, Giulio Antonelli
Journal: Clinical Gastroenterology and Hepatology (2022)

Artificial Intelligence (AI) could support cost-saving strategies for colonoscopy because of its accuracy in the optical diagnosis of colorectal polyps. However, AI must meet predefined criteria to be implemented in clinical settings.An approved computer-aided diagnosis (CADx) module for differentiating between adenoma and nonadenoma in unmagnified white-light colonoscopy was used in a consecutive series of colonoscopies. For each polyp, CADx output and subsequent endoscopist diagnosis with advanced imaging were matched against the histology gold standard. The primary outcome was the negative predictive value (NPV) of CADx for adenomatous histology for ≤5-mm rectosigmoid lesions. We also calculated the NPV for AI-assisted endoscopist predictions, and agreement between CADx and histology-based postpolypectomy surveillance intervals according to European and American guidelines.Overall, 544 polyps were removed in 162 patients, of which 295 (54.2%) were ≤5-mm rectosigmoid histologically verified lesions. CADx diagnosis was feasible in 291 of 295 (98.6%), and the NPV for ≤5-mm rectosigmoid lesions was 97.6% (95% CI, 94.1%-99.1%). There were 242 of 295 (82%) lesions that were amenable for a leave-in-situ strategy. Based on CADx output, 212 of 544 (39%) would be amenable to a resect-and-discard strategy, resulting in a 95.6% (95% CI, 90.8%-98.0%) and 95.9% (95% CI, 89.8%-98.4%) agreement between CADx- and histology-based surveillance intervals according to European and American guidelines, respectively. A similar NPV (97.6%; 95% CI, 94.8%-99.1%) for ≤5-mm rectosigmoids was achieved by AI-assisted endoscopists assessing polyps with electronic chromoendoscopy, with a CADx-concordant diagnosis in 97.2% of cases.In this study, CADx without advanced imaging exceeded the benchmarks required for optical diagnosis of colorectal polyps. CADx could help implement cost-saving strategies in colonoscopy by reducing the burden of polypectomy and/or pathology.gov registration number: NCT04884581.
Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks
Authors: Jacob W. Freimer, Oren Shaked, Sahin Naqvi, Nasa Sinnott-Armstrong, Arwa Kathiria, Christian M. Garrido, Amy F. Chen, Jessica T. Cortez, William J. Greenleaf, Jonathan K. Pritchard, Alexander Marson
Journal: Nature Genetics (2022)
Next‐generation pathology detection of T cell–antigen‐presenting cell immune synapses in human liver allografts
Authors: Michelle A. Wood‐Trageser, Drew Lesniak, Alessandro Gambella, Kayla Golnoski, Sandy Feng, John Bucuvalas, Alberto Sanchez‐Fueyo, A. Jake Demetris
Journal: Hepatology (2022)

Abstract Background and Aims In otherwise near‐normal appearing biopsies by routine light microscopy, next‐generation pathology (NGP) detected close pairings (immune pairs; iPAIRs) between lymphocytes and antigen‐presenting cells (APCs) that predicted immunosuppression weaning failure in pediatric liver transplant (LTx) recipients (Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients [iWITH], NCT01638559). We hypothesized that NGP‐detected iPAIRs enrich for true immune synapses, as determined by nuclear shape metrics, intercellular distances, and supramolecular activation complex (SMAC) formation. Approach and Results Intralobular iPAIRs (CD45 high lymphocyte–major histocompatibility complex II + APC pairs; n = 1167, training set) were identified at low resolution from multiplex immunohistochemistry–stained liver biopsy slides from several multicenter LTx immunosuppression titration clinical trials (iWITH; NCT02474199 (Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (ARTEMIS); Prospective Longitudinal Study of iWITH Screen Failures Secondary to Histopathology). After excluding complex multicellular aggregates, high‐resolution imaging was used to examine immune synapse formation ( n = 998). By enriching for close intranuclear lymphocyte–APC distance (mean: 0.713 μm) and lymphocyte nuclear flattening (mean ferret diameter: 2.1), SMAC formation was detected in 29% of iPAIR‐engaged versus 9.5% of unpaired lymphocytes. Integration of these morphometrics enhanced NGP detection of immune synapses (ai‐iSYN). Using iWITH preweaning biopsies from eligible patients ( n = 53; 18 tolerant, 35 nontolerant; testing set), ai‐iSYN accurately predicted (87.3% accuracy vs. 81.4% for iPAIRs; 100% sensitivity, 75% specificity) immunosuppression weaning failure. This confirmed the presence and importance of intralobular immune synapse formation in liver allografts. Stratification of biopsy mRNA expression data by immune synapse quantity yielded the top 20 genes involved in T cell activation and immune synapse formation and stability. Conclusions NGP‐detected immune synapses (subpathological rejection) in LTx patients prior to immunosuppression reduction suggests that NGP‐detected (allo)immune activity usefulness for titration of immunosuppressive therapy in various settings.
Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b
Authors: Mariavittoria D’Acierno, Roberta Resaz, Anna Iervolino, Rikke Nielsen, Donato Sardella, Sabrina Siccardi, Vincenzo Costanzo, Luciano D’Apolito, Yoko Suzumoto, Daniela Segalerba, Simonetta Astigiano, Alessandra F. Perna, Giovambattista Capasso, Alessandra Eva, Francesco Trepiccione
Journal: Journal of the American Society of Nephrology (2022)

Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires KRT. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype.We utilized an inducible mouse model of GSD1b, TM-G6PT-/-, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and thus to prevent glycogen accumulation, we administered an SGLT2-inhibitor, dapagliflozin, to TM-G6PT-/- mice.In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase-I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis toward lysis and by restoring expression levels of the main proximal tubule functional markers.We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat patients with GSD1b.
Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial
Authors: John M Pagel, Jacob D Soumerai, Nishitha Reddy, Deepa Jagadeesh, Anastasios Stathis, Adam Asch, Huda Salman, Vaishalee P Kenkre, Alexia Iasonos, Judith Llorin-Sangalang, Joanne Li, Andrew D Zelenetz
Journal: The Lancet Oncology (2022)
Effect of pre-resection biopsy on detection of advanced dysplasia in large nonpedunculated colorectal polyps undergoing endoscopic mucosal resection
Authors: Michael X. Ma, David J. Tate, Mayenaaz Sidhu, Simmi Zahid, Michael J. Bourke
Journal: Endoscopy (2022)

BACKGROUND : Pre-resection biopsy (PRB) of large nonpedunculated colorectal polyps (LNPCPs, ≥ 20 mm) is often performed before referral for endoscopic mucosal resection (EMR). How this affects the EMR procedure is unknown. METHODS : This was a retrospective analysis of a prospectively collected cohort of patients with LNPCPs referred for EMR between 2013 to 2016 at an Australian tertiary center. Outcomes were differences between PRB and EMR histology, and effects of PRB on the EMR procedure. RESULTS: Among 586 LNPCPs, lesions that underwent PRB were larger (median 35 vs. 30 mm; P < 0.007), and more commonly morphologically flat or slightly elevated (P = 0.01) compared with lesions without PRB. PRB histology was upstaged in 26.1 %, downstaged in 13.8 %, and unchanged in 60.1 % after EMR. Sensitivity of PRB was 77.2 % (95 %CI 71.1-82.4) for low grade dysplasia (LGD) and 21.2 % (95 %CI 11.5-35.1) for high grade dysplasia (HGD). Where EMR specimen showed HGD, PRB had detected LGD in 76.9 %. Where EMR specimen showed cancer, PRB had detected dysplasia only. PRB was associated with more submucosal fibrosis (P = 0.001) and intraprocedural bleeding (P = 0.03). EMR success or recurrence was not affected. CONCLUSIONS: Routine PRB of LNPCP did not reliably detect advanced histology and may have affected EMR complexity. PRB should be utilized with caution in guiding endoscopic management of LNPCPs.